To develop effective vaccines and immune therapies for retroviral infections, biologic and immunologic variables influencing the equilibrium between virus and host must be elucidated. Ongoing studies include the nature of immune responses elicited by vaccines, biologic and molecular characterization of novel human immunodeficiency virus type 1 (HIV-1) isolates, and effects and immunologic and biologic consequences of selection pressures on viral variability. Following immunization of rhesus macaques with attenuated poxvirus HIV-1 or HIV-2 recombinants and protein boosters, humoral and cellular immune responses were elicited, although neither activity correlated with protection. Further study of the HIV-2 macaque model suggested that neutralizing antibodies may be associated with protection. Adenovirus HIV-1 recombinants have been shown to elicit humoral, cellular, and mucosal immunity in the chimpanzee model. Prior adenovirus serostatus and the number of recombinant immunizations modulate immune responses. A novel hemagglutinin molecule with a V3 loop insert elicits high titered neutralizing antibodies in guinea pigs and rhesus macaques, and may prove useful as a booster immunogen. To develop targeted HIV vaccines, the prevalence of HIV subtypes in geographic locales must be known. HIV-1, not HIV-2, was shown to be prevalent in the West African nation of Nigeria. Biologic and molecular characterization of Nigerian HIV-1 isolates revealed a novel subtype. Molecular epidemiologic studies of isolates prevalent in Nigeria are proceeding. Viral variability presents a major obstacle to development of an effective HIV vaccine. HIV escape mutants arise from multiple pathways including the V3 loop and the CD4 binding domain on gp120. The context of envelope segments also influences neutralization. A revertant escape mutant revealed functional and immunologic relationships between the CD4 binding region, leucine zipper region, fusion domain, and a gp41 region hidden after envelope oligomerization. To avoid immune escape, immune strategies should target conserved, functionally important regions, so that mutation would lead to a non- infectious virus.